Citations

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) was the first study to evaluate effectiveness/safety of low-sodium oxybate (LXB; Xywav®) >9 g/night (outside the recommended range: 6–9 g/night). This analysis evaluated changes in patient-reported hypersomnolence measures in participants with narcolepsy taking LXB >9 g/night compared with LXB 9 g/night. Methods DUET was a phase 4, prospective, open-label study with screening, 8-day LXB 9 g/night (9g-baseline), titration/optimization, stable-dose, and 8-day end-of-treatment (EOT) optimized LXB >9 g/night (up to 12g; >9g-EOT) periods. Patient-reported measures included Epworth Sleepiness Scale (ESS), electronic sleep diaries (completed daily during 9g-baseline and >9g-EOT; subjective total sleep time [TST], number of awakenings, sleep efficiency [TST divided by time in bed], sleep quality [5-point scale; “very good” to “very poor”], and how rested/refreshed the participant felt upon awakening [5-point scale; “very well” to “not at all”]), Karolinska Sleepiness Scale (KSS; administered 90 minutes post-polysomnography awakening at 9g-baseline and >9g-EOT), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10). LSM differences (95% CI) from 9g-baseline to >9g-EOT (nominal P-values) were 9g-baseline-adjusted. Results Forty-eight participants took LXB >9g (mean±SD age: 39.2±10.9 years; 62.5% female). Total stable-dose LXB (mean±SD) was 11.1±1.0 g/night (n=45). From 9g-baseline to >9g-EOT, ESS scores improved (LSM [95% CI]: –3.1 [–4.2, –1.9]; P< 0.0001; n=44), nocturnal TST increased (0.3h [0.1, 0.4]; P=0.0163; n=26), sleep efficiency increased (3.8% [1.7, 5.9]; P=0.0011; n=26), and number of awakenings remained stable (–0.2 [–0.7, 0.3]; P=0.3959; n=26). Percentage of participants rating sleep quality as “very good”/”good” increased from 26.9% (9g-baseline) to 61.5% (>9g-EOT), as did rested sleep (“very well”/”well”/”somewhat” rested) from 57.7% to 69.2%, respectively. From 9g-baseline to >9g-EOT, KSS scores decreased (–0.9 [–1.4, –0.4]; P=0.0004; n=39); FOSQ-10 scores also increased (1.3 [0.5, 2.0]; P=0.0014; n=40). Of 48 participants, 36 (75.0%) experienced ≥1 TEAE (mostly mild/moderate and 1 serious [syncope, unrelated to treatment]). No changes in respiratory polysomnography measures were observed. Conclusion Participants with narcolepsy who optimized to LXB >9 g/night, relative to 9 g/night, reported increased sleep quality and restfulness that paralleled improvements in daytime sleepiness and daytime functioning. TEAEs were consistent with those at lower dosages. Support (if any) Jazz Pharmaceuticals

Abstract Introduction People with idiopathic hypersomnia often experience sleep inertia, characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening. This post-hoc analysis of the DUET study (NCT05875974) evaluated objective and subjective sleep inertia in participants with idiopathic hypersomnia taking low-sodium oxybate (LXB; Xywav®) stratified by patient-reported ideal nighttime sleep duration (with [>9h] and without [≤9h] long sleep need [LSN]), based on Idiopathic Hypersomnia Severity Scale (IHSS) item 1. Methods DUET was a phase 4, prospective, open-label study of LXB with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness), administered BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before/after PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, in LSN subgroups, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 46 enrolled participants with idiopathic hypersomnia, 45 had BL IHSS data; 24 reported LSN and 21 reported no LSN. Most (with/without LSN) were female (100.0%/61.9%) and White (91.7%/76.2%); 20/24 and 19/21 completed the study. Based on PVT lapses, objective sleep inertia ±SE (with/without LSN) at BL was 17.0±4.2/4.2±2.8, and at EOT was 0.0±na/2.0±0.9 (BL-to-EOT changes [95% CI]: −17.0 [−25.5, −8.5] and −2.2 [−6.9, 2.5]). Based on KSS, subjective sleep inertia ±SE (with/without LSN) at BL was 6.5±0.3/5.1±0.5, and at EOT was 0.81±0.5/1.5±0.6 (BL-to-EOT changes [95% CI]: −5.7 [−6.7, −4.7] and −3.5 [−4.5, −2.6]). Sleep inertia dissipation time constants ±SE were 2.7±1.1h (PVT) and 13.9±3.8h (KSS). TEAEs were consistent with the known LXB safety profile. Conclusion Participants with idiopathic hypersomnia experienced subjective and objective sleep inertia at BL, with prolonged dissipation after awakening. Objective BL sleep inertia was particularly severe in participants with LSN (>9h). After LXB treatment, notable improvements in objective and subjective sleep inertia were observed for both subgroups. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Sleep inertia (characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening) is a core idiopathic hypersomnia symptom and may also be experienced by individuals with narcolepsy. Sleep inertia in individuals with narcolepsy is not well studied. This post-hoc analysis of the DUET study (NCT05875974) evaluated sleep inertia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) subgroups of the DUET narcolepsy cohort. Methods DUET was a phase 4, prospective, open-label study with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness); both administered at BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before and after the PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, for NT1 and NT2, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 55 enrolled participants with narcolepsy, 26 and 29 had NT1 and NT2, respectively. Most (NT1/NT2) were female (73.1%/72.4%) and White (73.1%/86.2%); 16/26 and 18/29 completed the study. Based on PVT lapses, objective sleep inertia ±SE (NT1/NT2) at BL was 33.1±6.2/14.9±3.2, and at EOT was 8.3±1.7/3.2±1.1 (BL-to-EOT changes [95% CI]: −24.8 [−35.5, −14.1] and −11.8 [−17.4, −6.1]). Based on KSS ratings, subjective sleep inertia ±SE (NT1/NT2) at BL was 1.1±0.6/1.1±0.5, and at EOT was 0.8±0.5/1.3±0.5 (BL-to-EOT changes [95% CI]: −0.3 [−1.9, 1.2] and 0.2 [−1.3, 1.6]). Sleep inertia dissipation time constants ±SE were 1.6±0.3h (PVT) and 0.4±0.1h (KSS) for the overall cohort. TEAEs were consistent with the known LXB safety profile. Conclusion Participants with narcolepsy, especially NT1, demonstrated objective sleep inertia at BL. Participants with NT1 or NT2 showed substantial improvements in objective sleep inertia with LXB treatment. Support (if any) Jazz Pharmaceuticals

OBJECTIVE Protocols for intraoperative mapping during awake craniotomy vary widely. The aim of this study was to evaluate how the number and type of intraoperative neuropsychological paradigms administered via NeuroMapper, a tablet-based platform, during awake glioma surgery affect positive mapping rates, return to work (RTW), and oncological outcomes. Factors associated with the operative duration and early postoperative neurological deficits were of additional interest. METHODS This single-center retrospective study included patients with diffuse low- and high-grade gliomas who underwent awake craniotomy with NeuroMapper-guided mapping between 2018 and 2024. Primary outcomes were RTW, progression-free survival (PFS), and overall survival (OS); operative duration and early postoperative deficits were secondary outcomes. Covariate balancing propensity score (CBPS) analysis was used to address confounding by tumor grade, with all postweighting standardized mean differences < 0.10. A weighted logistic regression model assessed RTW, and CBPS-weighted Cox models assessed PFS and OS. Linear regression was used to analyze intraoperative variables, operative duration, and early postoperative deficits. RESULTS Of 189 patients included in the analysis, 65 had LGG (median age 39 years) and 124 had HGG (median age 56 years). Mapping complexity varied, with 1–6 tasks used (median 4). Weighted multivariate logistic regression analysis identified the following independent predictors of RTW: preoperative Karnofsky Performance Status score ≥ 80 (OR 1.37, p = 0.039), absence of recurrent disease (OR 0.30, p < 0.001), use of 5–6 paradigms (OR 1.54, p = 0.047), positive mapping (OR 2.41, p = 0.017), and subtotal resection (OR 4.43, p = 0.002). Intraoperative seizure, early postoperative deficit, and the resection technique were not significant. IDH mutation status was associated with improved PFS (HR 0.15, p < 0.001), while subtotal resection was associated with worsened PFS (HR 3.00, p < 0.001). Positive mapping was associated with better OS (HR 0.57, p = 0.04). The operative duration was unaffected by mapping variables but was longer in patients with obesity (β = 0.28, p = 0.038). CONCLUSIONS Positive NeuroMapper-guided mapping of more diverse linguistic functions was associated with RTW and longer OS. Additionally, mapping complexity did not prolong surgery times, supporting potential standardization.

ABSTRACT Aims Exercise capacity is a powerful predictor of cardiovascular risk. In patients unable to exercise, body composition analysis can potentially be used to estimate cardiorespiratory fitness. We developed a body composition “fitness” score, then validated its utility in two external populations. Methods and Results We included patients from four sites undergoing single photon emission computed tomography (SPECT) and twelve sites undergoing positron emission tomography (PET). We quantified body composition using deep learning. We evaluated associations between body composition and good exercise capacity (defined as completing ≥7 minutes on a Bruce protocol) then developed a body composition “fitness” score. We then assessed the associations of “fitness” score with exercise capacity and all-cause mortality in external populations. In total, 36471 patients were included with median age 67 (interquartile range 58 – 74). Median skeletal muscle density was higher among patients with good exercise capacity. In the external SPECT population, the body composition “fitness” score had higher prediction performance for good exercise capacity (AUC 0.771, 95% CI 0.752 – 0.789) than age (AUC 0.717, p<0.01). In the external PET population, high body composition “fitness” score was associated with lower cardiovascular death (adjusted hazard ratio 0.70, 95% CI 0.62 – 0.79, p<0.001). Conclusions We demonstrated that a comprehensive body composition “fitness” score could identify patients with good cardiorespiratory fitness. This approach transforms routinely acquired CT data into a surrogate marker of fitness which can be applied in patients undergoing PET, or other CT imaging, where exercise testing is not performed. Graphical Abstract Overview of study design. The overall population (n=36471) was split as outlined above. Body composition was analyzed from available computed tomography imaging. The distribution of body composition measures were analyzed in the combined single photon emission computed tomography (SPECT) populations. A body composition “fitness” score was derived to predict good exercise capacity in the internal population, with associations assessed in the two external testing populations.

Background The middle meningeal artery (MMA) has emerged as an endovascular route for treating chronic subdural hematoma (CSDH), meningioma, and refractory headaches. The third ARISE roundtable convened experts from neurology, neurosurgery, neuroradiology, industry, and regulatory agencies to develop consensus guidance on current evidence for MMA-based therapies Methods Over 50 experts participated in a multi-stakeholder discussion. Evidence from randomized and observational studies, early-phase interventional series, and preclinical work was reviewed. Breakout groups focused on four domains: (1) MMA embolization (MMAE) for CSDH, (2) preoperative embolization of meningiomas, (3) MMA-targeted therapies for headache, and (4) transvascular access for endovascular drainage of subdural hematomas. Consensus recommendations were developed by a writing committee Results Randomized trials support MMAE as an adjunct to surgery or medical management for selected patients with non-acute, symptomatic CSDH to reduce recurrence, progression, and reoperation. Evidence remains insufficient to support MMAE for acute or asymptomatic subdural hematomas. For meningioma, observational data suggest that preoperative embolization in experienced centers can reduce blood loss and operative time and may delay recurrence in large, hypervascular tumors with predominant dural or external carotid supply; primary embolization and intra-arterial oncologic therapies remain investigational. Early series of MMA-directed lidocaine infusion for refractory migraine, status migrainosus, and post-subarachnoid hemorrhage headache show short-term benefit, highlighting the need for controlled trials. Preclinical and first-in-human studies of combined MMAE and transvascular drainage for CSDH demonstrate high technical success, rapid radiographic and clinical improvement, and no early recurrences Conclusion The MMA represents a vascular pathway for an expanding spectrum of neurointerventional therapies.

Importance Amblyopia is the leading cause of monocular decreased best-corrected vision in children. Early detection and intervention are key for optimal treatment outcomes; however, limited access to pediatric eye specialists may hinder timely care and affect visual outcomes. Given the shortage of specialty-trained eye care professionals in the US, there is need to support comprehensive eye care professionals who are willing to examine and treat children with amblyopia. Objective A panel from the Pediatric Eye Disease Investigator Group synthesized relevant literature and incorporated consensus opinion where direct evidence was lacking to create the Amblyopia Navigator Decision-Support Instrument, a free, web-based amblyopia decision support tool for eye care professionals. Evidence Review The decisions related to optimal diagnostic measures, pass/refer criteria, and management recommendations were informed by 147 publications. In areas where direct evidence was lacking, guidance was supplemented with clinical trial protocols or existing professional guidelines. When data were conflicting or unavailable, recommendations were established through committee consensus. A single reviewer independently performed standardized (though not systematic) literature reviews to avoid missing pertinent recent publications. Findings Presented are the process used, supporting evidence, and recommendations for testing methods, refractive correction, amblyopia treatment options, treatment adjustments, and monitoring schedules. Conclusions and Relevance Because amblyopia is common and typically responds well to treatment, decision support tools that optimize its management could increase access to pediatric eye care by facilitating earlier detection, enabling broader participation of primary eye care professionals, and ultimately improving visual outcomes. Through this work and the development of the forthcoming free, web-based application version, Amblyopia Navigator Decision-Support Instrument, the Pediatric Eye Disease Investigator Group has created decision support tools designed to assist optometrists and ophthalmologists in the care of children aged 3 to 17 years with amblyopia.

Introduction: Young-onset esophageal adenocarcinoma (EAC) often presents at advanced stages and is associated with poor outcomes. We aimed to examine the epidemiology of young-onset Barrett’s esophagus (BE) using the TriNetX database. Methods: Young-onset BE patients (age 18 to younger than 50 y) with esophagogastroduodenoscopy (EGD) within 1 year before index BE diagnosis between 2014 and 2023 were included. Negative binomial regression was used to evaluate incident-time trends, and logistic regression to assess for independent predictors of young-onset BE. Results: BE diagnosis was present in 76,691 (3.3%) of 2,337,786 patients that underwent EGD, of which 14,120 (18%) had prevalent young-onset BE. BE dysplasia/EAC was present in 6% of young-onset patients at initial diagnosis. Conventional BE risk factors also predicted young-onset BE: GERD (OR=2.4), White race (OR=2.4), male sex (OR=2.2), smoking (OR=1.2), and obesity (OR=1.1). Each additional risk factor increased the probability of BE prevalence by 74% in young patients versus 54% in older patients. The prevalence of young-onset BE was 4.5% with GERD and ≥3 additional risk factors, and 2.3% when ≥3 risk factors were present. Discussion: Young-onset BE accounts for 18% of all BE cases, demonstrates a striking 6% rate of dysplasia/neoplasia at initial diagnosis, and has a prevalence of 4.5% in those with GERD and ≥3 risk factors. These findings suggest that young-onset BE is an important patient population that merits further study. Additional studies are necessary to study the cost-effectiveness of BE screening in younger patients with multiple risk factors.